Neurologic disorders are abnormal conditions of the nervous system. They can be categorized according to the structure or primary location affected, the nature of the dysfunction or the primary cause (e.g., genetic disorder, injury, infection). Some neurologic disorders, like Parkinson's disease and stroke, are well-known while others are very rare. One recent study by the World Health Organization (WHO) found that neurologic disorders account for almost 11% of total global disease burden worldwide. Collectively, the burden of neurologic disorders is hard to overstate, and includes direct health care costs, disability, quality of life and lost productivity. Alzheimer's disease alone drains more than $148 billion from the U.S. economy each year. The burden of neurologic disorder is expected to increase on a global basis, as demographic changes in the world's most populous countries will result in a significant increase in the number of persons with neurodegenerative diseases over the next few decades.
NMDA Receptors
There are four classes of excitatory amino acids (EAA) receptors in brain that mediate neuronal activity: NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid), kainate and metabotropic receptors. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are widely localized on neuronal and non-neuronal cells, regulating a broad spectrum of processes in the central and peripheral nervous system. The NMDA subtype of glutamate-gated ion channels mediates excitatory synaptic transmission between neurons in the central nervous system (Traynelis et al. Pharmacol Rev (2010) 62:405-96).
NMDA receptors are composed of GluN1, GluN2 (A, B, C, and D), and GluN3 (A and B) subunits, which determine the functional properties of native NMDA receptors. Co-expression of the GluN1 subunit with one or more GluN2 subunits is required to form functional channels. In addition to glutamate binding on GluN2 subunits, the NMDA receptor requires the binding of a co-agonist, glycine at GluN1 subunits, to allow the receptor to function. A glycine binding site is also found on GluN3 subunits. At resting membrane potentials, NMDA receptors are largely inactive due to a voltage-dependent block of the channel pore by magnesium ions. Depolarization releases this channel block and permits passage of calcium and monovalent ions such as sodium ions.
NMDA receptors participate in a wide range of both physiological and pathological processes in the central nervous system and are found in neurons throughout the brain including the cortico-limbic regions which have been postulated to play a role in emotional functions, anxiety and depression (Tzschentke T M (2002) Amino Acids 23:147-152). Many studies have demonstrated antidepressant-like effects of various antagonists of the NMDA receptors. The antidepressant-like activity of competitive, uncompetitive, and non-competitive antagonists of NMDA receptors has been reported (Trullas, et al. (1990) Eur J Pharmacol 185:1-10; Layer et al., (1995) Pharmacol Biochem Behavi 52:621-627; Decollogne, et al. (1997) Pharmacol Biochem Behav 58:261-268; Przegaliñski, et al. (1997) Neuropharmacology 36:31-37; Przegaliñski, et al. (1998) Pol J Pharmacol 50: 349-354; Skolnick P Eur J Pharmacol 375:31-40; Berman et al., (2000) Biol Psychiatry 47:351-4; Kroczka, et al. (2000) Pol J Pharmacol 52:403-406; Skolnick, et al. (2001) Pharmacol Res 43:411-423; Kroczka, et al. (2001) Brain Res Bull 55:297-300; Poleszak, et al. (2004) Pharmacol Biochem Behav 78:7-12; Zarate et al., (2006) Arch Gen Psychiatry 63:856-64; Poleszak, et al. (2007) Pharmacol Biochem Behav 88:158-164; Poleszak, et al. (2007) Pharmacol Rep 57:654-658; Maeng et al., (2008) Biol Psychiatry 63:349-52; Preskorn et al., (2008) J Clin Psychopharm 28:631-637, Li et al., (2010) Science 329: 959-64, Diazgranados et al (2010) Arch Gen Psych 67: 793-802. Poleszak, et al. showed that the NMDA receptor binding of certain antagonists, specifically CGP 37849 and L-701,324, are directly related to their antidepressant-like effects (Poleszak, et al. (2007) Pharm. Reports 59:595-600).
NMDA receptor antagonists may also be beneficial in the treatment of chronic pain. For example, it has been reported that NMDA receptor antagonists produce an analgesic effect under certain conditions (Wong, et al. (1995) Acta Anaesthesiologica Sinica 33, 227-232). Nerve ligation, carrageenan-induced hyperalgesia, and wind-up pain in rats were all relieved by non-competitive, competitive, and GluN2B selective NMDA receptor antagonists (Boyce et al., (1999) Neuropharmacol 38: 611-623). Chronic pain, including neuropathic pain such as that due to injury of peripheral or central nerves, has often proved very difficult to treat. Treatment of chronic pain with ketamine and amantadine has proven beneficial, and it is believed that the analgesic effects of ketamine and amantadine are mediated by block of NMDA receptors. Several case reports have indicated that systemic administration of amantadine or ketamine substantially reduces the intensity of trauma-induced neuropathic pain. Small-scale double blind, randomized clinical trials corroborated that amantadine could significantly reduce neuropathic pain in cancer patients (Pud et al. (1998), Pain 75:349-354) and ketamine could reduce pain in patients with peripheral nerve injury (Felsby et al. (1996), Pain 64:283-291), peripheral vascular disease (Perrson et al. (1998), Acta Anaesthesiol Scand 42:750-758), or kidney donors (Stubhaug et al. (1997), Acta Anaesthesiol Scand 41:1124-1132). “Wind-up pain” produced by repeated pinpricking was also dramatically reduced. These findings suggest that central sensitization caused by nociceptive inputs can be prevented by administration of NMDA receptor antagonists.
NMDA receptor antagonists can also be beneficial in the treatment of Parkinson's Disease (Blandini and Greenamyre (1998), Fundam Clin Pharmacol 12:4-12), brain cancers (Takano, T., et al. (2001), Nature Medicine 7:1010-1015; Rothstein, J. D. and Bren, H. (2001) Nature Medicine 7:994-995; Rzeski, W., et al. (2001), Proc. Nat'l Acad. Sci. 98:6372), and neuropsychiatric disorders including depressive disorders and bipolar disorders, which affect more than 60 million Americans each year. Depression affects approximately one in six individuals in the United States at some point in their lives (Hyman, (2008) Nature 455:890-893). The World Health Organization (2001) ranks depression as the single most common cause of disability for individuals aged 15-44. Therapies for depression include a diversity of antidepressant medications, psychotherapy, and for those failing these measures, electroconvulsive therapy and transcranial magnetic stimulation. Unfortunately, an estimated 30-40% of affected individuals are resistant to these current, diverse therapies (Rush et al., (1998) J Clin Psychiatry 59(suppl 20):73-84.). Functional antagonists of the NMDA receptor complex exhibit antidepressant-like activity in models of depression. Trullas and Skolnick demonstrated the antidepressant activity of AP-7, MK-801 and ACPC in the mouse forced swim test (FST) and tail suspension test (TST) (Trullas R, Skolnick P (1990) Eur J Pharmacol 185:1-10). A number of reports have confirmed and extended this finding to also include GluN2B NMDA receptor antagonists (Layer et al., (1995) Pharmacol Biochem Behavi 52:621-627. Maeng et al., (2008) Biol Psychiatry 63:349-52, Li et al., (2010) Science 329: 959-64).
U.S. Pat. No. 7,019,016 to Pfizer provides methods for treating certain disorders including depression which comprise administration of certain GluN2B subunit selective NMDA antagonists. The disorders that can be treated by the invention include hearing loss, vision loss, neurodegeneration caused by epileptic seizures, neurotoxin poisoning, Restless Leg Syndrome, multi-system atrophy, non-vascular headache, and depression.
U.S. Pat. No. 5,710,168 claims the use of certain compounds having GluN2B subunit selectivity for treating a disease or condition which is susceptible to treatment by blocking of NMDA receptor sites, including traumatic brain injury, spinal cord trauma, pain, psychotic conditions, drug addiction, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence, and ischemic events arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.
U.S. Pat. No. 6,479,553 to AstraZeneca provides certain compounds, in particular memantine, budipine, amantidine, 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, dextromethorphan and NPS 1506, and the compounds disclosed in EP 279 937 and EP 633 879, specifically (S)-1-phenyl-2-(2-pyridyl)ethanamine as potentially useful as antidepressant agents. In particular, the compounds were expected to be useful in the treatment of depression associated with neurodegenerative disorders such as Alzheimer's disease.
U.S. Pat. No. 6,432,985 to Hoffman La-Roche provides certain neuroprotective substituted piperidine compounds with activity as NMDA GluN2B subtype selective antagonists
PCT Publication WO 06/017409 to Merck & Co. provides certain 1,3-disubstituted heteroaryl compounds are N-methyl-D-aspartate receptor antagonists useful for treating neurological condition e.g. pain, Parkinson's disease, Alzheimer's disease, anxiety, epilepsy and stroke.
PCT Publication WO 02/072542, to Emory University describes a class of pH-dependent NMDA receptor antagonists that exhibit pH sensitivity tested in vitro using an oocyte assay and in an experimental model of epilepsy.
PCT Publication WO 09/006,437, to Emory University and NeurOp, Inc., describes a class of pH sensitive NMDA antagonists for treatment of disorders including stroke, traumatic brain injury, neuropathic pain, epilepsy, and related neurologic events or neurodegeneration.
While NMDA-receptor antagonists might be useful to treat a number of disorders, to date, dose-limiting side effects have prevented clinical use of NMDA receptor antagonists for these conditions. Thus, despite the potential for glutamate antagonists to treat many serious diseases, the severity of the side effects have caused many to abandon hope that a well-tolerated NMDA receptor antagonist could be developed (Hoyte L. et al (2004) Curr. Mol. Med. 4(2): 131-136; Muir, K. W. and Lees, K. R. (1995) Stroke 26:503-513; Herrling, P. L., ed. (1997) “Excitatory amino acid clinical results with antagonists” Academic Press; Parsons et al. (1998) Drug News Perspective II: 523 569).
pH Sensitive NMDA Receptors
The extracellular pH is highly dynamic in mammalian brain, and influences the function of a multitude of biochemical processes and proteins, including glutamate receptor function. The pH-sensitivity of the NMDA receptor has received increasing attention for at least two reasons. First, the IC50 value for proton inhibition of pH 7.4 places the receptor under tonic inhibition at physiological pH. Second, pH changes are extensively documented in the central nervous system during synaptic transmission, glutamate receptor activation, glutamate receptor uptake, and prominently during pathological states such as ischemia and seizures (Siesjo, B K (1985), Progr Brain Res 63:121-154; Chesler, M (1990), Prog Neurobiol 34:401-427; Chesler and Kaila (1992), Trends Neurosci 15:396-402; Amato et al. (1994), J Neurophysiol 72:1686-1696). During stroke, transient ischemia leads to a dramatic drop of pH to 6.4-6.9 (Mutch & Hansen (1984) J Cereb Blood Flow Metab 4: 17-27, Smith et al. (1986) J Cereb Blood Flow Metab 6: 574-583; Nedergaard et al. (1991) Am J Physiol 260(Pt3): R581-588; Katsura et al (1992a) Euro J Neursci 4: 166-176; and Katsura & Siesjo (1998) “Acid base metabolism in ischemia” in pH and Brain function (Eds Kaila & Ransom) Wiley-Liss, New York). In addition to ischemia, there are various other examples of situations in which pH changes under normal and abnormal conditions, including neuropathic pain (Jendelova & Sykova (1991) Glia 4: 56-63; Chvatal et al. (1988) Physiol Bohemoslov 37: 203-212; Sykova et al. (1992) Can J Physiol Pharmacol 70: Suppl S301-309; Sykova & Svoboda (1990) Brain Res 512: 181-189) and Parkinson's disease, which may result in a lower local pH (see, for example, Chesler (1990) Prog Neurobiol 34: 401-427, Chesler & Kaila (1992) Tr Neurosci 15: 396-402, and Kaila & Chesler (1998) “Activity evoked changes in extracellular pH” in pH and Brain function (eds Kaila and Ransom). Wiley-Liss, New York).
Acidification also occurs during seizures (Siesjo et al (1985) J Cereb Blood Flow Metab 5: 47-57; Balestrino & Somjen (1988) J Physiol 396: 247-266; and Xiong & Stringer (2000) J Neurophysiol 83: 3519-3524). In addition, other types of brain injury can result in acidification (Kaku et al. (1993), Science 260:1516-1518; Munir and McGonigle (1995), J Neurosci 15:7847-7860; Vornov et al. (1996), J Neurochem 67:2379-2389; Gray et al. (1997), J Neurosurg Anesthesiol 9:180-187; O'Donnell and Bickler (1994), Stroke 25:171-177; reviewed by Tombaugh and Sapolsky (1993), J Neurochem 61:793-803) and seizure maintenance (Balestrino and Somjen (1988), J Physiol (Lond) 396:247-266; Velisek et al. (1994), Exp Brain Res 101:44-52).
PCT Publication WO 06/023957 to Emory University describes processes for selection of a compound which may be useful in the treatment of an ischemic injury or a disorder that lowers the pH in a manner that activates the NMDA receptor antagonist.
There remains a need for improved compounds and methods for the treatment of neurologic disorders that have reduced toxicity. In particular, there is a need for improved treatments for neuropsychiatric disorders, neurodegenerative disorders and other neurological disorders of diverse origin that have enhanced efficacy and reduced side effects.